Developing a path forward for sodium-glucose cotransporter (SGLT) inhibitor treatment for heart and kidney disease in people with type 1 diabetes (T1D) is essential. This article offers the perspective of experts from the fields of endocrinology, nephrology, and cardiology on available data for the efficacy and safety of SGLT inhibitors in T1D, how the far more extensive data from people with type 2 diabetes (T2D) and people without diabetes would be expected to translate to T1D, and what steps are required to advance toward regulatory approvals and clinical uptake of SGLT inhibitors in T1D for heart and kidney disease. Our conclusion is that the mechanisms driving efficacy of SGLT inhibitors for heart and kidney disease in T2D and nondiabetic disease are likely applicable to T1D and that in light of the data supporting efficacy in these populations, registrational trials in T1D might not require powering for traditional event-based outcomes and investigators may instead rely on suitable surrogate end points, allowing for more feasible trials. Investigators in these trials must also carefully collect data associated with diabetic ketoacidosis (DKA), the critical risk of SGLT inhibitor use in T1D. DKA risk mitigation is essential for SGLT inhibitor use in T1D; protocols to mitigate risk have been developed, but rigorous data on their effectiveness are lacking. We describe a roadmap to advance SGLT inhibitors for T1D heart and kidney disease, which includes the use of feasible trial designs based on surrogate end points and rigorous safety protocols to minimize DKA events.
Overweight and obesity are forecasted to impact more than 80% of US adults by 2050,1 and represent leading risk factors for cardiovascular, kidney, and metabolic (CKM) diseases.2 These trends, combined with population aging, underscore the potential for an expanding burden of multiple long-term CKM conditions.3,4 However, the extent to which obesity is associated with multiple CKM conditions among US adults has not been rigorously evaluated, and further evidence may inform clinical, research, and public health policy efforts. In this analysis of the National Health and Nutrition Examination Survey (NHANES), we evaluated the association between body mass index (BMI) and multiple long-term CKM conditions.
OBJECTIVE Single islet autoantibody-positive individuals exhibit highly variable risk for type 1 diabetes progression. We evaluated whether metabolic measures identify those at higher progression risk. RESEARCH DESIGN AND METHODS Among confirmed single autoantibody-positive first and second degree relatives of persons with type 1 diabetes enrolled in the TrialNet Pathway to Prevention Natural History study, we used Cox proportional hazards models to assess associations between metabolic measures and time to progression, defined as the development of multiple autoantibody-positive or stage 3 type 1 diabetes. Random forest models were used to estimate the relative importance of each variable. Analyses were conducted in the overall cohort and stratified by age (0-8, >8-16, and >16 years). RESULTS Single autoantibody-positive persons exhibited wide variation in metabolic function. Measures incorporating both oral glucose tolerance test (OGTT)-stimulated glucose and C-peptide to assess β-cell dysfunction showed strong and consistent associations with progression across age groups and antibody profiles. Associations for traditional risk factors, isolated glucose or c-peptide measures, or indices of insulin resistance differed by age and autoantibody type. Data-driven cutoffs for combined metabolic measures identified small subsets at very high risk (>50% 2-year progression), and large low-risk groups with <10% 5-year progression. CONCLUSIONS β-cell dysfunction is present in many single autoantibody-positive individuals and is associated with an increased risk of disease progression. Incorporating stimulated measures of β-cell function alongside age and autoantibody profiles may enable more personalized monitoring, help identify persons most likely to benefit from disease-modifying therapies and delineate lower-risk individuals who require less intensive surveillance.
Objective: To compare the risk of motility-related gastrointestinal (GI) events associated with commonly prescribed opioids among adults with type 2 diabetes (T2D) receiving glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy, a population in whom the GI safety of concomitant opioid use has not been well characterized. Research Design and Methods: Population-based new-user cohort study using US insurance claims (2016–2025) among adults with T2D receiving GLP-1RA who initiated oxycodone, hydrocodone, or tramadol. We evaluated a composite of motility-related GI events, including severe constipation, bowel obstruction, and gastroparesis, and estimated 30-day weighted absolute risks, risk ratios (RR), and risk differences (RD) using propensity score matching weights. Results: Among 411,188 patients (mean age 62.8 years; 53.8% female), 24.4% initiated oxycodone, 48.5% hydrocodone, and 27.1% tramadol. The weighted 30-day absolute risk of motility-related GI events was 0.51% for oxycodone, 0.35% for hydrocodone, and 0.33% for tramadol. Oxycodone was associated with a higher risk than hydrocodone (RR 1.48, 95% CI 1.30–1.69; RD 0.17, 95% CI 0.11–0.22) and tramadol (RR 1.55, 95% CI 1.33–1.79; RD 0.18, 95% CI 0.12–0.24). Hydrocodone and tramadol showed similar risks (RR 1.05, 95% CI 0.91–1.21; RD 0.02, 95% CI −0.03–0.06). Conclusions: Among adults with T2D on GLP-1RA, initiation of oxycodone was associated with higher short-term risks of severe constipation and bowel obstruction compared with hydrocodone or tramadol. We did not observe differences in the risk of gastroparesis. Risks were similar between patients initiating hydrocodone and tramadol, although variation across secondary analyses warrants cautious interpretation.
OBJECTIVE:The Baricitinib in New-Onset Type 1 Diabetes (BANDIT) trial showed that baricitinib treatment for 48 weeks preserved β-cell function and lowered insulin requirements and glucose in recent-onset type 1 diabetes. We aimed to determine the durability of these effects following treatment cessation. RESEARCH DESIGN AND METHODS:The following posttreatment outcomes of the randomized, double-blind, placebo-controlled BANDIT trial were analyzed: C-peptide and glucagon responses to a mixed meal, HbA1c, continuous glucose monitoring (CGM) measures, CD8+ T-cell phenotype and function, and adverse events. RESULTS:Of 91 randomized participants, 88 (58 baricitinib and 30 placebo) completed the week 96 follow-up. Mean ± SEM C-peptide was significantly greater in baricitinib-treated participants at week 72 (0.54 ± 0.05 vs. 0.38 ± 0.06 pmol/mL; P = 0.015) but not at week 96 (0.43 ± 0.05 vs. 0.35 ± 0.06 nmol/L; P = 0.336). No significant between-group differences in insulin dose, HbA1c, or CGM measures were observed during follow-up. Post hoc comparisons showed that when the study drug was ceased at week 48, baricitinib-treated adults (n = 28) experienced full preservation of β-cell function whereas C-peptide decreased relative to baseline by 0.09 pmol/mL in baricitinib-treated children (n = 32; P = 0.022). Baricitinib did not resolve paradoxical glucagon increase after a mixed meal. Decreased frequency and cytokine signaling of effector memory CD8+ T cells observed at week 48 resolved by week 96. CONCLUSIONS:The benefits of oral baricitinib in type 1 diabetes wane over 48 weeks following treatment cessation. Durable benefit is likely to require continuous treatment.
OBJECTIVE:Selective glucagon-like protein 1 receptor (GLP-1R) agonists reduce body weight and improve cardiometabolic risk factors. However, whether dual GLP-1R and glucagon receptor (GCGR) agonism modifies these cardiometabolic effects remains unclear. Here, we assessed the effects of dual GLP-1R/GCGR agonists on cardiometabolic risk factors across randomized controlled trials. RESEARCH DESIGN AND METHODS:In this random-effects meta-analysis, Medical Literature Analysis and Retrieval System Online (MEDLINE), Embase, and Cochran Central Register of Controlled Trials (CENTRAL) were searched from database inception to 21 June 2026 for randomized controlled trials evaluating clinical efficacy of dual GLP-1R/GCGR agonists in adults with cardiometabolic disease with a treatment duration ≥12 weeks. The primary outcome was placebo-corrected change in body weight from baseline to end of treatment. Secondary outcomes were changes in waist circumference, atherogenic lipids (total cholesterol, LDL cholesterol, and triglycerides), glycated hemoglobin, and hemodynamic outcomes. Prespecified subgroup analyses evaluated effect modification by dose, treatment indication, and the use of an active comparator (selective GLP-1R agonists). RESULTS:A total of 6,593 records were identified, and 16 trials comprising 6,611 participants (47.3% male) were included. Dual GLP-1R/GCGR agonists significantly reduced body weight compared with placebo (-7.44% [95% CI -9.44, -5.43]; -7.27 kg [95% CI -9.28, -5.27]). Weight loss was accompanied by improvements across all cardiometabolic risk factors. Compared with selective GLP-1R agonists, dual GLP-1R/GCGR agonists were associated with a greater reduction in triglycerides (-0.28 mmol/L [95% CI -0.50, -0.06]). CONCLUSIONS:Dual GLP-1R/GCGR agonists consistently improved cardiometabolic risk factors across randomized clinical trials and may provide metabolic benefits beyond selective GLP-1R agonists. These findings support further evaluation in large-scale outcome studies.
Asia confronts a disproportionately high diabetes burden, characterized by aggressive pathophysiology and early-onset complications. For addressing this crisis, established therapeutic agents are actively leveraged across Asia via multifaceted approaches, e.g., developing fixed-dose combinations to improve adherence or optimizing drug structures to enhance therapeutic profiles. Concurrently, Asian innovators are advancing emerging target-based agent classes into clinical use, including glucagon-like peptide 1 multiagonists, glucokinase activators, pan-peroxisome proliferator-activated receptor modulators, AMP-activated protein kinase/NOD-like receptor family pyrin domain-containing 3 dual targeted compound, glimins-class oral small molecule, and G-protein-coupled receptor 119 receptor agonist, etc. Technologies such as antisense oligonucleotide (ASO) inhibitors targeting glucagon receptor, stem cell therapy, and microbiome-based glycemic management are also being clinically validated in Asia. Meanwhile, devices such as continuous glucose monitoring, automated insulin delivery systems, and noninvasive glucose monitors are advancing toward broader clinical adoption. This review critically synthesizes Asia's contemporary strategies against diabetes, spanning from the optimization of established target-based agents to the breakthroughs of novel therapeutics and the advancement of maturing technologies and devices. This evolution reflects Asia's accelerating transition from a major clinical trial hub and product consumer to a global driver and leader in innovative glucose-lowering drug development. Propelled by pioneering drug innovators, surging research and development investment, and robust multistakeholder collaboration across industry, academia, and health care, the region is fostering a dynamic innovation ecosystem. Through synergistically advancing the research and application of glucose-lowering therapeutics alongside context-adapted implementation, Asia's practical experience delivers a referable approach for diabetes management across the globe and promotes sustained innovation within diabetology.
Objective Waist circumference–based measures can improve diabetes risk assessment beyond body mass index (BMI). Yet, evidence to guide their integration into screening guidelines in low- and middle-income countries (LMICs) is limited, particularly to assess risk among individuals at intermediate BMI ranges. We evaluated the associations of waist circumference (WC), relative fat mass (RFM), and BMI with diabetes across 82 LMICs. Research Design and Methods We analyzed individual-level data from nationally representative surveys across 82 LMICs, comprising 598,883 adults aged ≥25 years with a BMI of 18.5–29.9 kg/m². Associations of anthropometric measures with diabetes were estimated as risk ratios using Poisson regression and area under the curve (AUC), stratified by sex and geographic region. Results Pooled diabetes prevalence was 9.1% (95% confidence interval: 8.51–9.68). Overall, risk of diabetes was greatest for WC and RFM at the highest quintile, compared to BMI. The AUC for WC and RFM as a classifier of diabetes status was higher than the AUC for BMI in men (AUC: WC 0.69, RFM 0.69, BMI 0.64) and women (AUC: WC 0.69, RFM 0.69, BMI 0.63). Generally, the AUC for RFM was higher than the AUC for BMI and either higher or equal to WC across regions and sex. Conclusions WC and RFM outperformed BMI as classifiers of diabetes status among adults with a BMI of 18.5–29.9 kg/m2 across 82 LMICs. Inclusion of WC-based measures in diabetes screening guidelines could improve timely diabetes detection and resource allocation in LMICs among individuals at intermediate BMI ranges.
Gestational diabetes mellitus (GDM) has long been viewed as a metabolic condition first recognized during pregnancy. However, research now demonstrates that underlying metabolic abnormalities are detectable during the preconception period in individuals who subsequently develop GDM and that GDM carries long-term implications for both mothers and offspring. In this article, I provide an overview of the work that my colleagues and I have conducted over the past 25 years, aimed at understanding when GDM risk emerges, how risk can be modified, and how intrauterine exposure to hyperglycemia and its treatment influences health across the life course. This work spans population-based epidemiology, preconception biomarker studies, efficacy prevention trials, and pragmatic interventions embedded within an integrated health care system. Together, these findings affirm Norbert Freinkel’s concept of fuel-mediated teratogenesis and underscore the need for precision prevention and treatment strategies that address biological, behavioral, and social determinants of health risk factors.
